# In Vivo Gene Targeting to Treat Inherited Bone Disease

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $349,800

## Abstract

   
DESCRIPTION (provided by applicant): Mutations in bone stem cells can impair bone metabolism and regeneration. Osteogenesis imperfect (OI) is the most common form of genetic bone disease and characterized by bone fragility with clinical manifestations varying from a mild increase in fractures to severe bone deformities and death. Individuals with OI have mutations that alter procollagen structure or production and lead to abnormal collagen fibril formation disrupting bone development and renewal. Treatment options for OI are limited and do not alleviate the complications seen in OI. Our recent work has demonstrated that AAV gene targeting vectors can disrupt the mutant collagen alleles that cause OI and that targeted cells produced normal collagen and formed bone. While these results indicate the effectiveness of genomic editing with targeting frequencies approaching 1%, an enhancement of AAV gene targeting is required to provide more robust in vivo genetic manipulations. Here we will expand upon our successes and propose three lines of investigations to develop a therapeutic approach for patients with inherited bone disease. First we will modify collagen genes using a CRISPR-AAV system that will allow for the disruption or correction of genes that cause OI in vivo. Second, we will investigate whether genetically corrected bone stem cells have a growth advantage in vivo and how TGF-beta signaling affects the extra-skeletal manifestations of bone disease. Finally we will conduct a series of experiments in a preclinical rabbit model to establish
the optimal gene targeting delivery protocol. Successful completion of this proposal will lead to an improved understand of TGF-beta signaling and stem cell kinetics in bone and advance AAV gene targeting toward a clinical trial.

## Key facts

- **NIH application ID:** 9906850
- **Project number:** 5R01AR067707-05
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** David R Deyle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $349,800
- **Award type:** 5
- **Project period:** 2015-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906850

## Citation

> US National Institutes of Health, RePORTER application 9906850, In Vivo Gene Targeting to Treat Inherited Bone Disease (5R01AR067707-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9906850. Licensed CC0.

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